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| - Novel, Nonpeptidic Cyanamides as Potent and Reversible Inhibitors of HumanCathepsins K and L
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| - Compounds containing a 1-cyanopyrrolidinyl ring were identified as potent and reversibleinhibitors of cathepsins K and L. The original lead compound 1 inhibits cathepsins K and Lwith IC50 values of 0.37 and 0.45 μM, respectively. Modification of compound 1 by replacementof the quinoline moiety led to the synthesis of N-(1-cyano-3-pyrrolidinyl)benzenesulfonamide(2). Compound 2 was found to be a potent inhibitor of cathepsins K and L with a Ki value of50 nM for cathepsin K. Replacement of the 1-cyanopyrrolidine of compound 2 by a 1-cyanoazetidine increased the potency of the inhibitor by 10-fold. This increase in potency is probablydue to an enhanced chemical reactivity of the compound toward the thiolate of the active siteof the enzyme. This is demonstrated when the assay is performed in the presence of glutathioneat pH 7.0 which favors the formation of a GSH thiolate anion. Under these assay conditions,there is a loss of potency in the 1-cyanoazetidine series due to the formation of an inactivecomplex between the GSH thiolate and the 1-cyanoazetidine inhibitors. 1-Cyanopyrrolidinylinhibitors exhibited time-dependent inhibition which allowed us to determine the associationand dissociation rate constants with human cathepsin K. The kinetic data obtained showedthat the increase of potency observed between different 1-cyanopyrrolidinyl inhibitors is dueto an increase of kon values and that the association of the compound with the enzyme fits anapparent one-step mechanism. 13C NMR experiments performed with the enzyme papainshowed that compound 2 forms a covalent isothiourea ester adduct with the enzyme. Aspredicted by the kinetic analysis, the addition of the irreversible inhibitor E64 to the enzyme−cyanopyrrolidinyl complex totally abolished the signal of the isothiourea bond as observed by13C NMR, thereby demonstrating that the formation of the covalent bond with the active sitecysteine residue is reversible. Finally, compound 2 inhibits bone resorption in an in vitro assayinvolving rabbit osteoclasts and bovine bone with an IC50 value of 0.7 μM. 1-Cyanopyrrolidinerepresents a new class of nonpeptidic compounds that inhibit cathepsin K and L activity andproteolysis of bone collagen.
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